Interleukin-3 (IL-3)-dependent murine 32D cells do not detectably express epidermal growth factor receptors (EGFRs) and do not proliferate in response to EGF, heregulin (HRG) or other known EGF-like ligands. Previously, we reported that EGF specifically binds to and can be crosslinked to 32D transfectants co-expressing ErbB2 and ErbB3 (32D.E2/E3). EGF, BTC and HRG also induced receptor tyrosine phosphorylation, activation of downstream signaling molecules and proliferation of 32D.E2/E3 cells. These results provide evidence that ErbB2/ErbB3 binding sites for EGF and BTC are formed by a unique mechanism that requires co-expression of two distinct receptors. In a separate study, 32D transfectants were generated expressing human ErbB4 alone or in combination with ErbB2. As demonstrated in previous studies, 32D cells expressing only ErbB4 responded mitogenically to NRG and BTC. Surprisingly, EGF also induced significant DNA synthesis and TGF-alpha was negligibly mitogenic on 32D cells expressing ErbB4. Although coexpression of ErbB2 with ErbB4 did not significantly alter DNA synthesis in response to NRG or BTC, it greatly enhanced mitogenesis elicited by EGF and TGF-alpha. This study provides evidence that the ability of ErbB4 to mediate signal transduction through ErbB ligands is broader than previously assumed and can be profoundly altered by concomitant expression of ErbB2. - breast cancer, cell proliferation, growth factors, Protein Kinase, Proto-oncogenes, receptor signaling estrogens, receptors, - Human Tissues, Fluids, Cells, etc.